title: Deletion of the proline-rich region of the murine metastasis susceptibility gene Brd4 promotes epithelial-to-mesenchymal transition- and stem cell-like conversion.
abstract: The bromodomain-containing chromatin-modifying factor BRD4 is an inherited susceptibility gene for breast cancer progression and metastasis, but its functionality in these settings has yet to be explored. Here we show that deletion of either of the BRD4 bromodomains had modest effects on the metastatic suppression ability of BRD4. In contrast, expression of the natural short isoform of BRD4 that truncates the protein after the SEED domain restored progression and metastatic capacity. Unexpectedly, deletion of the proline-rich region induced mesenchymal-like conversion and acquisition of cancer stem cell-like properties, which are mediated by the carboxy-terminal P-TEFb binding domain. Deletion of this proline-rich region also induced a gene expression signature that predicted poor outcome in human breast cancer data sets and that overlapped G3 grade human breast tumors. Thus our findings suggest that BRD4 may be altering the predisposition of tumors to undergo conversion to a more de-differentiated or primitive state during metastatic progression.
authors.affiliation: Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jude
authors.initials: J
authors.lastname: Alsarraj
authors.forename: Renard C
authors.initials: RC
authors.lastname: Walker
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Webster
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Geiger
authors.forename: Nigel P S
authors.initials: NP
authors.lastname: Crawford
authors.forename: R Mark
authors.initials: RM
authors.lastname: Simpson
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.forename: Kent W
authors.initials: KW
authors.lastname: Hunter
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D055232:Proline-Rich Protein Domains / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins